High intensity focused ultrasound (HIFU) is a non-invasive therapy that focuses an ultrasound energy on a deep target tissue through a high-intensity focused-ultrasound transducer placed outside the human body so as to accurately damage the deep target tissue without damaging the tissue on the ultrasound path and the normal tissue surrounding the target zone. The thermal effect of ultrasound is mainly utilized in the traditional thermal ablation mode of HIFU. While, the histotripsy mode mainly utilizes the cavitation effect and mechanical effect of HIFU to disintegrate the target tissue into micron-sized fragments (homogenization for tissue cutting), which can be applied in tumor ablation. It can also be extended to applications such as therapies of kidney calculus, arrhythmia and thrombolysis.
Compared to the thermal ablation mode, the histotripsy has the following advantages. 1) The histotripsy overcomes the defects of the thermal ablation mode which is difficult to effectively damage adjacent tissues of great vessels due to the heat-sink effect, thereby increasing the effectiveness of the HIFU. 2) An absorbable liquid by tissue is formed after the therapy of the histotripsy mode. Compared to the coagulation damage generated in the thermal ablation, the liquefied target tissue is easy to be absorbed by periphery tissue, and the postoperative recovery is faster. The histotripsy is more suitable for clinical application. 3) The cavitation cloud and boiling bubbles generated during the therapy of the histotripsy can be monitored by B-mode ultrasonic device in real-time so as to conveniently evaluate the therapy process.
The existing histotripsy techniques mainly includes two modes, which are a histotripsy using an extremely high intensity ultrasound with a length of several-microsecond pulse train to generate cavitation cloud and a histotripsy using an ultrasound with a length of several-millisecond pulse train to generate boiling bubbles. The cavitation cloud histotripsy (CH) process needs to control the formation of shock wave in a focal zone, and the negative acoustic pressure is required to exceed the cavitation threshold. The shock wave is reflected by a single microbubble to form a large negative acoustic pressure, and is superimposed with an incident wave to form the cavitation cloud. A research team of the University of Michigan has proposed and developed a therapy model to homogenize soft tissue using an ultra-high intensity pulsed ultrasound to generate cavitation and mechanical effects. U.S. Pat. No. 6,309,355 B1 (Cain, titled “Method and assembly for performing ultrasound surgery using cavitation”) disclosed a method for treating tissue lesion under ultrasound induction using a pulse sequence with a duration of less than 50 μs in 2001. Further, Cain (U.S. Pat. No. 8,057,408 B2, titled “Pulsed cavitational ultrasound therapy”) proposed that the therapy process includes the subprocesses of initiation, maintenance, therapy, and feedback. The therapeutic parameters such as the acoustic pressure amplitude and duty cycle of the ultrasound and the pulse repetition frequency in the subprocess are controlled to produce different cavitation biological effects to improve the controllability of the cavitation cloud of the histotripsy mode. Further, Cain (US Application Publication 20130090579 A1, titled “Pulsed cavitational therapeutic ultrasound with dithering”) proposed dissipating cavitation bubbles between two groups of pulses by a pulsed ultrasound with a duty cycle of less than 1%, thereby eliminating “cavitation memory”. So that the distribution of cavitation bubbles in the focal zone is more random and the damage region is more uniform. Further, Cain (WO 2015027164 A1, titled “Histotripsy using very short ultrasound pulses”) proposed a microtripsy method using very short ultrasound pulses of less than 2 cycles. The method increases the peak negative acoustic pressure to exceed the intrinsic cavitation threshold so as to generate a damage with a length less than one wavelength, and the damage region is precisely controllable. However, excessive acoustic pressure has an impact on the surrounding tissue, which puts pressure on clinical applications. The boiling histotripsy mainly uses an ultrasound with a length of several-millisecond pulse train to generate rapid heating boiling of the tissue, and when the boiling bubbles in the shockwave field, a strong mechanical action is generated to damage the tissue. Michael S. Canney, et al. (U.S. Pat. No. 8,876,740 B2, titled “Methods and systems for non-invasive treatment of tissue using high intensity focused ultrasound therapy”) disclosed a method and apparatus for generating boiling bubbles in target tissue using an ultrasound with a length of several-millisecond pulse train. Khokhlova Vera, et al. (WO 2015148966 A1, titled “Boiling histotripsy methods and systems for uniform volumetric ablation of an object by high intensity focused ultrasound waves with shocks”) disclosed methods and apparatus for guiding an ultrasound to generate boiling bubbles at different points of a target tissue for tissue lesion.
The synergistic mechanism by superposing two ultrasound waves with different frequency is also applied in ultrasound therapy. Kuang-Wei Lin (WO 2015138781 A1, titled “Frequency compounding ultrasound pulses for imaging and therapy”) proposed a histotripsy method using a low frequency (100 kHz to 1 MHz) ultrasound and a high frequency (2 to 10 MHz) ultrasound to simultaneously act on a target tissue and controlling a pulse delay of two frequencies to form a unipolar pulse. G. Iernetti (“Enhancement of high-frequency cavitation effects by a low frequency stimulation” (Ultrasounds Sonochemistry, vol. 4, pp. 263-268, 1997)) utilized a high frequency ultrasound of 700 kHz and a low frequency ultrasound of 20 kHz to enhance cavitation effects. The low frequency ultrasound is used to amplify the cavitation effect of high frequency ultrasound at different cavitation stages in the target tissue region. The method of superposing the low frequency ultrasound to the high frequency ultrasound with frequencies of a kHz order has several shortcomings as follows. (1) The ultrasound with a frequency of a kHz order is large in volume of focal zone and cannot accurately damage the target tissue. (2) The ultrasound with a frequency of a kHz order has a low ultrasound amplitude in the focal zone and cannot effectively damage the target tissue.
The existing methods of histotripsy still have the following deficiencies. 1. The required peak acoustic pressure is large, and the cavitation cloud histotripsy (CH) requires a peak negative acoustic pressure of 15-25 MPa, and a peak positive acoustic pressure of greater than 80 MPa. The peak negative acoustic pressure required for boiling bubble (BH) is 10-15 MPa, and the peak positive acoustic pressure is required of greater than 40 MPa, which brings certain pressure on clinical safety. 2. The pulse duration of the cavitation cloud histotripsy is only about 10 μs, the duty cycle is about 1%, the ultrasound excitation time required for the formation of a lesion is longer, and the therapy efficiency is lower. 3. The shape of the lesion formed by the boiling histotripsy is difficult to control, usually resulting an excessive damage at a position of the near the transducer.
In view of the above deficiencies, a method for controlling a histotripsy using a confocal fundamental and harmonic superposition combined with hundred-microsecond ultrasound pulses is proposed to improve the efficiency and safety of the therapy.